Preparation of beta-collidine

ABSTRACT

THE PREPARATION OF B-COLLIDINE FROM METHYL VINYL KETONE AND AN AMINE SUCH AS, FOR EXAMPLE, BENZYLAMINE, THROUGH VARIOUS INTERMEDIATES, FOR EXAMPLE, 3-ACETYL-1BENZYL - 1,2,5,6 - TETRAHYDRO-4-METHYLPYRIDINE, 3-ACETYL1,2,5,6 - TETRAHYDRO - 4 - METHYLPYRIDINE, 3 - ACETYL-4METHYLPYRIDINE, 1 - BENZYL - 3 - (1-HYDROXYETHYL)-1,2,5,6TETRAHYDRO- 4 - METHYLPYRIDINE, 3-(1-HYDROXYETHYL)-4METHYLPYRIDINE AND 1-BENZYL-3-ETHYLENE-1,2,3,6-TETRAHYDRO - 4-METHYLPYRIDINE, IS DESCRIBED. B-COLLIDINE, I.E., 3ETHYL-4-METHYLPYRIDINE, IS USEFUL IN THE SYNTHESIS OF, FOR EXAMPLE, DIHYDROQUINIDINE.

United States Patent 015cc 3,663,554 Patented May 16, 1972 3,663,554PREPARATION OF B-COLLIDINE .luerg Albert Walter Gutzwiller, Bloomfield,and Milan Radoje Uskokovic, Upper Montclair, N .J., assignors toHolfmann-La Roche Inc., Nutley, NJ. No Drawing. Original applicationJan. 22, 1968, Ser. No.

699,334. Divided and this application Mar. 27, 1970,

Ser. No. 23,503

Int. Cl. C07d 31/08 US. Cl. 260290 I Claims ABSTRACT OF THE DISCLOSURECROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionof US. patent application Ser. No. 699,334, filed Jan. 22, 1968, now US.Pat. 3,553,221.

BRIEF SUMMARY OF THE INVENTION The invention relates to a process forpreparing B- collidine which comprises the steps of:

(a) Condensing an amine, such as ammonia, benzylamine or a substitutedbenzylamine with methyl vinyl ketone and dehydrating the reactionproduct;

(b) Aromatizing the product of step (a) and, when R is other thanhydrogen, simultaneously debenzylating the product of step (a) to yield3-acetyl-4-methylpyridine; and

(c) Reducing the product of step (b) to form ,B-collidine.

When the amine utilized in step (a) is benzylamine or substitutedbenzylamine, another aspect of the invention comprises the steps of:

(d) Reducing the product of step (a); and

(e) Simultaneously dehydrating, debenzylating and aromatizing theproduct of step (d) to form B-collidine.

In still another aspect, the invention comprises the steps of:

(f) Aromatizing the product of step (d);

(g) Debenzylating the product of step (f); and

(h) Reducing the product of step (g) to form 5- collidine.

In a further aspect, the invention relates to a process which comprisesthe steps of:

(i) Dehydrating the product of step (d); and

(j) Simultaneously debenzylating and aromatizing the reaction product ofstep (i) to form S-collidine.

In still a further aspect, the invention relates to a process whichcomprises the steps of:

(k) Reducing the product of step (b) with a metal hydride; and

(h) Catalytically hydrogenating the product of step (k) to formli-collidine.

In its final aspect, the invention relates to the hereinafter describedintermediates of the Formulas III, VI, VII, VIII and IX.

DETAILED DESCRIPTION OF THE INVENTION B-Collidine is useful in thepreparation of, for example, dihydroquinine and dihydroquinidine [Rabeet al., Chem. Ber. 64, 2487 (1931)], 3,4-diethylpyridine [Taub et al.,J. Org. Chem. 30, 3229 (1965)], and diastereoisomeric 6,7-benzomorphans[Fullerton et al., J. Org. Chem., 27, 2554 (1962)].

The preparation of fi-collidine according to the invention may beexemplified by the following reaction schemes:

SCHEME I mill 2 W ly;

r or, II

\ are I III R CH3 o 035 ll i N c a l OKs IV a ll wherein R is selectedfrom the group consisting of hydrogen, benzyl, lower alkyl substitutedbenzyl, lower alkoxy substituted benzyl and halo substituted benzyl.

As used herein, the term lower alkyl denotes a straight or branchedchain hydrocarbon group containing 1-7 carbons, e.g., methyl, ethyl,propyl, isopropyl, butyl, tertiary, butyl, and the like; methyl ispreferred. The term lower alkoxy denotes a lower alkyl ether group inwhich the lower alkyl moiety is as described above; methoxy ispreferred. The term halogen denotes chlorine, bromine, fluorine andiodine; chlorine is preferred.

In Scheme I, Reaction (a), the preparation of the compound of FormulaIII, is carried out by condensing the amine of Formula I and methyl'vinyl ketone, preferably in the presence of an inert solvent, such asan alkanol, for example, methanol, ethanol or the like, and subsequentlydehydrating the resulting reaction product, for example, with an acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, para-toluenesulfonic acid, or the like, preferably in a suitable inert solvent, forexample, methanol, isopropanol, or the like. Preferably, one molarproportion of the amine is reacted with two molar proportions of themethyl vinyl ketone. Con- 'veniently, the reaction is carried out at atemperature in the range of room temperature and the boiling point ofthe mixture. However, higher or lower temperatures may be suitablyemployed. If desired, the crude reaction product may be recovered fromthe reaction mixture by conventional methods, such as, for example,extraction with ether or other suitable organic solvents. However, thefurther purification of this crude product is not essential foroperation of the process. The crude product as such may be utilized inthe subsequent reaction step.

Among the amines of Formula I which may be used in the process of theinvention are ammonia, benzylamine, p-methoxybenzylamine,p-chlorobenzylamine, pmethylbenzylamine and the like.

Reaction (b), the conversion of the compound of Formula III, wherein Ris benzyl or substituted benzyl, to the compound of Formula IV, iscarreid out by simultaneously debenzylating and dehydrogenating theproduct of reaction (a), wherein R is benzyl or substituted benzyl,utilizing a catalyst such as rhodium on carbon, Raney nickel, palladiumon carbon, or the like, in acetic acid alone or with a solvent such asbenzene. Conveniently, the reaction is carried out at a temperature inthe range of room temperature and the boiling point of the reactionmixture. Following completion of the reaction, the catalyst may beremoved by conventional methods, for example, filtration, decantation orthe like. If desired, the reaction product may be recovered aspreviously described in step (a). Again, recovery is not essential andthe reaction mixture as such may be subjected to step (c).

The conversion of the compound of Formula III, wherein R is hydrogen, iscarried out as above, except that debenzylation is omitted.

Reaction (c), the conversion of the compound of Formula IV, i.e.,3-acetyl-4methylpyridine, to the compound of Formula V, i.e.,fi-collidine, is carried out by reducing the product of Reaction (1))with hydrogen under pressure, for example, at 100 to 200 p.s.i., in thepresence of a reducing catalyst, such as palladium on carbon, Raneynickel, rhodium on carbon, or the like. Recovery of the fl-collidine maybe effected employing conventional methods, for example, conversion tothe acid addition salt, and crystallization.

SCllI-J-lE I;

mm H o 2 CH III GIL; 0!!

CH5 A (5 (e) E I A VI V wherein R is selected from the group consistingof benzyl, lower alkyl substituted benzyl, lower alkoxy substitutedbenzyl, and halo substituted benzyl.

In Scheme II, Reaction (a) is carried out under the conditionspreviously described for Reaction (a).

Reaction (d), the conversion of the compound of Formula IIIa to thecompound of Formula VI, is carried out utilizing a reducing agent, suchas a metal hydride, for example, sodium borohydride, lithium aluminumhydride, lithium borohydride, lithium aluminum-tri-t-butoxy hydride,diisobutyl aluminum hydride, potassium borohydride, and the like, in aninert organic solvent, for example, sodium borohydride in methanol orisopropanol, diisobutyl aluminum hydride in toluene, lithium aluminumtri-t-butoxy hydride in tetrahydrofuran, ether, diglyme or the like.Advantageously, the reaction is carried out at a temperature in therange of from about 0l00 C., preferably from about 20 to about 75 C. Thereaction product may be separated by conventional methods.

Reaction (e), the conversion of the compound of Formula VI top-collidine is carried out utilizing glacial acetic acid, alone or witha solvent such as benzene, and a catalyst such as rhodium on carbon,Raney nickel, palladium on carbon or the like. Advantageously, thereaction is conducted at reflux temperatures. However, it is possible toutilize temperatures in the range of room temperature to the refluxtemperature. Recovery of the fl-collidine may be effected as describedunder Reaction (c).

cu; OH. I

v: i (1) R1. in

CH3 CR1 0}! ACES I cg:

9 vrrr v1: {5 x (at) (s) cm, or;

H II wherein R is as previously described, and X is an anion ofinorganic acid such as hydrochloric acid, sulfuric acid, nitric acid andthe like.

In Scheme III, Reaction (f), the conversion of the compound of FormulaVI to the compound of Formula VIII, is carried out utilizing mercuricacetate in an aqueous solution of acetic acid. Advantageously, thereaction may be carried out at a temperature in the range of roomtemperature to C., preferably at 50-90 C. The product is recovered as asalt of an inorganic acid such as hydrochloric acid, sulfuric acid andthe like.

Reaction (g), the conversion of the compound of Formula VHI to thecompound of Formula IX, i.e., 3-(l-hydroxyethyl)-4-methylpyridine, iscarried out utilizing a catalyst such as, for example, palladium oncarbon, rhodium on carbon, Raney nickel or the like, in the presence ofan inert solvent, for example, ethanol, propanol, butanol or the like,and hydrogenating at atmospheric pressure.

Reaction (h), the conversion of the compound of Formula IX tofi-collidine, is carried out utilizing a catalyst, such as, for example,palladium on carbon, rhodium on carbon, Raney nickel, in the presence ofan inert solvent such as ethanol, propanol, butanol or the like andhydrogen under pressure, for example, 100-200 p.s.i. Advantageously, thereaction is carried out at temperatures from 0-100 C., preferably fromabout 25-75 C.

Reaction (i), the conversion of the compound of Formula VI to thecompound of Formula VII, i.e., l-benzyl-3-ethylene-l,2,3,6-tetrahydro-4-methylpyridine, is carried out utilizinga dehydrating agent, such as an acid, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, paratoluene sulfonic acid or the like.Advantageously, the reaction may be carried out at reflux temperatures.However, temperatures from 0 C. to reflux temperatures may be utilized.

Reaction (j), the conversion of the compound of Formula VII tofi-collidine, is carried out utilizing a catalyst such as rhodium oncarbon, Raney nickel or palladium on carbon, in a mixture of glacialacetic acid and benzene. Advantageously, the reaction is carried out ata temperature of from about 0 C. to reflux temperatures, preferably atreflux temperatures. Recovery may be effected as described underReaction (c).

SCHEME IV In Scheme IV, Reaction (k), the conversion of the compound ofFormula IV to the compound of Formula 1X, i.e.,3-(l-hydroxyethyl)-4-methylpyridine, is carried out utilizing a reducingcatalyst such as previously described under Reaction ((1), in an inertsolvent.

Reaction (h) is carried out as previously described.

Conveniently, the various intermediates hereinbefore mentioned, may bereacted in the form of the free base or as the acid addition salt with,for instance, pharmaceutically acceptable acids such as hydrochloricacid, sulfuric acid and the like. The acid addition salts or thecorresponding free base, whichever is desired, can be prepared utilizingconventional procedures.

Furthermore, those of the intermediates hereinbefore mentioned whichform racemic mixtures can be utilized as such or can be separated intotheir fractions utilizing conventional procedures.

The following non-limiting examples further illustrate the invention.All temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 3-acetyl-1-benzyl-1,2,5,6-tetrahydro-4-methylpyridine oxalate To a solution containing 107 g. of benzylamine in500 ml. of methanol, stirred and cooled on an ice bath, a solutioncontaining 154 g. of freshly distilled methyl vinyl ketone in 500 ml. ofmethanol was added dropwise. The reaction mixture was allowed to attainroom temperature and was stirred overnight. After evaporation to drynessin vacuo, 236.5 g. of oily residue were obtained. The residue wasdissolved in 800 ml. of isopropanol saturated with hydrogen chloridegas. The resulting solution was heated at 60 for 1.5 hours, andthereafter evaporated to dryness in vacuo. The 267.5 g. of oily residueobtained were dissolved in 300 ml. of water, made alkaline with 2 Naqueous sodium carbonate (600 ml.), and extracted with five 500 ml.portions of ether. The combined extracts were washed with two 100 ml.portions of water, dried over anhydrous magnesium sulfate and evaporatedin vacuo to yield 144 g. of crude oily3-acetyl-l-benzyl-1,2,5,6-tetrahydro-4-methylpyridine. The crude productwas distilled under reduced pressure (0.025 mm.) and three fractionswere collected: first fraction distilled at 50-144 and weighed 34.2 g.;second fraction distilled at 144-147 and weighed 123 g.; and thirdfraction distilled at 143 144" and weighed 9.9 g. The second fractionWas dissolved in 200 ml. of methanol and to it were added 48.9 g. ofoxalic acid to yield 98 g. of oxalate having an M.P. of 143.8-144.8.

6 EXAMPLE 2 Preparation of 1-benzyl-3-(1-hydroxyethyl)-l,2,5,6-tetrahydro-4-methylpyridine To a solution containing 6.5 g. of3-acetyl-1-benzyl- 1,2,5,6-tetrahydro-4-methylpyridine (made from theoxalate of Example 1) in 50 ml. of isopropanol, 1.074 g. of sodiumborohydride were added. The reaction mixture was stirred for one hour atroom temperature and then for three and a half hours at 60. Thereafter,the reaction mixture was neutralized with 2 ml. acetic acid andevaporated to dryness. To the residue were added 75 ml. of water. Theresulting suspension was extracted with six 250 ml. portions of ether.The ether extracts were combined, washed with three 50 ml. portions ofaqueous 2 N sodium carbonate and once with 50 ml. of water, dried overanhydrous magnesium sulfate and evaporated to dryness to yield 6.23 g.of oily racemic 1- benzyl 3l-hydroxyethyl)-1,2,5,6-tetrahydro-4-methylpyridine.

EXAMPLE 3 Preparation of 3-acetyl-4-methylpyridine hydrochloride Asolution containing 3.2 g. of 3-acetyl-1-benzyl-l,2,5,6-tetrahydro-4methylpyridine oxalate in 50 ml. of water was madealkaline with 12 ml. of aqueous 2 N sodium carbonate solution, and thenextracted with five ml. portions of ether. The ether extracts werecombined, washed with 25 ml. of water, dried over anhydrous magnesiumsulfate and evaporated to dryness in vacuo. The 2.64 g. of oily residueobtained were dissolved in 100 ml. of acetic acid benzene (1:1 volume)and 2 g. of 10 percent palladium on carbon were added. The resultingsuspension was refluxed 3 hours. Thereafter, the catalyst was removed byfiltration, and the filtrate was evaporated to dryness. The residue wasdissolved in 50 ml. of isopropanol saturated with hydrogen chloride gas.On evaporation, two crops, 0.834 g. and 0.109 g. of crystalline 3-acetyl-4-methylpyridine hydrochloride were obtained (55 percent yield),which after recrystallizations from isopropanol had an M.P. of 182.

In a manner analogous to Example 1, methyl vinyl ketone is reacted withammonia in place of benzylamine. The crude product containing3-acetyl-1,2,5,6-tetrahydro- 4-methylpyridine is aromatized using aceticacid and benzene (1:1 volume) and 10 percent palladium on carbon, in amanner analogous to Example 3 to yield 3-acetyl-4- methylpyridinehydrochloride.

EXAMPLE 4 Preparation of B-collidine hydrochloride To a solutioncontaining 1.7 g. of 3-acetyl-4-methylpyridine hydrochloride in 100 ml.of ethanol were added 1 ml. of conc. hydrochloric acid and 1.5 g. of 10percent palladium on carbon. The resulting suspension was hydrogenatedat 200 p.s.i. pressure and at a temperature of 50-60". Thereafter, thereaction mixture was filtered to yield 1.6 g. of crystallinefi-collidine hydrochloride, which after recrystallization from acetonehad a melting point of 158-166.

EXAMPLE 5 Preparation of racemic N-benzyl-3-(l-hydroxyethyl) -4-methylpyridinium chloride To a solution containing 2.31 g. of1-benzyl-3-(1-hydroxyethyl)-1,2,5,6-tetrahydro-4-methylpyridine in 168ml. of 50 percent aqueous acetic acid, 25.5 g. of mercuric acetate wereadded, and the reaction mixture was stirred at 7580 for 17 hours. Aftercooling to room temperature, the 8.62 g. of mercurous acetate thatformed were removed by filtration. The filtrate was saturated withhydrogen sulfide over a period of twenty minutes and the blackprecipitate obtained was removed by filtration. The resulting filtratewas evaporated to dryness, and the residue that formed was dissolved in100 ml. of isopropanol saturated with hydrogen chloride. The resultingsolution was evaporated to yield 2.38 g. (90.4 percent) of anhydrousN-benzyl-3-(1 hydroxyethyl)-4-methylpyridinium chloride.

EXAMPLE 6 Preparation of racemic 3-(1-hydroxyethyl)-4-methylpyridinehydrochloride To a solution containing 2.33 g. ofN-benzyl-3-(l-hydroxyethyl)-4-methylpyridinium chloride in 50 ml. ofethanol, 1 ml. of cone. hydrochloric acid and 1.5 g. of percentpalladium on carbon were added. The resulting mixture was hydrogenatedat atmospheric pressure. (The hydrogen uptake was 0.0103 mole.)Thereafter, the catalyst was removed by filtration, and the filtrate wasevaporated to dryness to yield 1.43 g. of crystalline3-(l-hydroxyethyl)-4-methylpyridine hydrochloride which afterrecrystallization from acetone had a melting point of 142.5144.

EXAMPLE 7 Preparation of racemic 3-(1-hydroxyethyl)-4- methylpyridinehydrochloride A solution containing 1.71 g. of 3-acetyl-4-methylpyridinehydrochloride in chloroform was shaken with a saturated aqueous solutionof potassium carbonate and then evaporated to yield 1 g. of free base.The free base was dissolved in ml. of isopropanol and reduced with 0.378g. of sodium borohydride at 60 for one hour. The reaction mixture wasacidified with 2 ml. of glacial acetic acid and evaporated to dryness.The residue was dissolved in water and its pH was adjusted to 8, with 2N sodium carbonate. The resulting suspension was extracted with four 80ml. portions of chloroform. The extracts were combined, washed with 50ml. of isopropanol saturated with hydrogen chloride and the resultingsolution was evaporated to dryness to yield 1.53 g. (88.5 percent) of3-(l-hydroxyethyl)-4-methylpyridine which after recrystallization fromacetone had a melting point of 147- 149.

EXAMPLE 8 Preparation of fi-collidine hydrochloride To a solutioncontaining 1.74 g. of 3-(1-hydroxyethyl)- 4-methylpyridine hydrochloridein 100 ml. of ethanol were added 1 ml. of cone. hydrochloric acid and1.5 g. of 10 percent palladium on carbon. This mixture was thenhydrogenated at 200 p.s.i. pressure and 50-60. The catalyst was removedby filtration and the filtrate evaporated to yield 1.5 g. (95.5 percent)of crystalline fl-collidine hydrochloride which after recrystallizationfrom acetone had a melting point of 150466".

EXAMPLE 9 Preparation of fl-collidine hydrochloride To a solutioncontaining 23 g. of1-benzyl-3-(1-hydroxyethyl)-1,2,5,6-tetrahydro-4-methylpyridine inl-liter of a 1:1 mixture of glacial acetic acid and benzene were added10 g. of 10 percent palladium on carbon. The reaction mixture wasrefluxed for 22 hours. The catalyst was separated by filtration, and thefiltrate was evaporated. The 21.6 g. of residual dark brown oil weredissolved in 100 ml. of isopropanol staturated with hydrogen chlorideand allowed to stand for two days at room temperature. Afterevaporation, 22.3 g. of dark brown solid residue were recrystallizedfrom acetone to yield 7.6 g. of [icollidine hydrochloride (48.5percent).

EXAMPLE 10 Preparation of l-benzyl-3-ethylene-1,2,3,6-tetrahydro-4-methylpyridine hydrochloride A solution containing 1.61 g. of racemic1-benzyl-3- (1-hydroxyethyl)-1,2,5,6-tetrahydro-4 methylpyridine inisopropanol saturated with hydrogen chloride gas was refluxed for 3.5hours. The resulting reaction mixture was evaporated to dryness to yield1.073 g. of crude l-benzyl-3-ethylene-l,2,3,6-tetrahydro4-methylpyridine hydrochloride which afterrecrystallization from acetone had a melting point of 212-214.

EXAMPLE 11 Preparation of fl-collidine hydrochloride To a solutioncontaining 2.13 g. (0.01 mole) of 1-benzyl-3-ethylene-1,2,3,6-tetrahydro 4 methylpyridine (free baseprepared freshly from hydrochloride) in 100 ml. of 1:1 mixture ofglacial acetic acid and benzene, 2 g. of 10 percent palladium on carbonwere added. After refluxing the reaction mixture for 16 hours, thecatalyst was separated by filtration and the filtrate evaporated todryness to yield 1 g. of oily residue. This oily residue was dissolvedin 8 ml. of conc. hydrochloric acid and ml. of methanol, and theresulting solution was evaporated to dryness. The residue which remainedwas dissolved in acetone, purified with charcoal and cooled andconcentrated to yield 0.33 g. of crystalline fi-collidine hydrochloride.

What is claimed is:

1. A process for preparing fi-collidine which comprises the steps of:

(A) condensing an amine of the formula RNH wherein R is selected fromthe group consisting of hydrogen, benzyl, lower alkyl substitutedbenzyl, lower alkoxy substituted benzyl, and halo substituted benzyl,with methyl vinyl ketone in the presence of an inert solvent andtreating the reaction product with a dehydrating agent selected from thegroup consisting of hydrochloric acid, hydrobromic acid, sulfuric acidand paratoluene sulfonic acid;

(B) producing 3-acetyl-4-methylpyridine by the step which consists oftreating the product of step (A) with a dehydrogenating, debenzylatingagent selected from the group consisting of rhodium on carbon, Raneynickel and palladium on carbon in the presence of acetic acid alone orin combination with benzene to yield 3-acetyl-4-methylpyridine; and

(C) treating the reaction product of step (B) with hydrogen underpressure in the presence of a reducing catalyst selected from the groupconsisting of rhodium on carbon, Raney nickel and palladium on carbon toyield p-collidine.

2. A process according to claim 1 wherein the aromatizing agent and thedebenzylating agent of step (B) is palladium on carbon in an aceticacid/benzene mixture.

3. A process according to claim 2 wherein the reducing catalyst of step(C) is palladium on carbon.

4. A process according to claim 3, wherein R is benzyl.

5. A process according to claim 4, wherein one molar proportion of amineis condensed with two molar proportions of methyl vinyl ketone.

References Cited UNITED STATES PATENTS 3,080,372 3/1963 Janssen et a1.260-294.7 2,765,311 10/1956 Horrobin et a1 260-290 2,765,310 10/ 1956Horrobin et a1. 260-290 OTHER REFERENCES Murata et al., J. Chem. Soc.Japan, Industrial Chem. Sec., vol. 58, pp. 387-88 (1955).

HENRY. R. JILES, Primary Examiner H. I. MORTAZ, Assistant Examiner U.S.Cl. X.R. 260290 H, 297 R

